Background and Significance: Prostate cancer (CaP) has a strong predilection for bone metastasis with other distant sites being only rarely involved. This observation supports Paget's "seed (cancer cell) and soil (organ of metastasis)" hypothesis which postulates that development of clinical metastases in a specific organ depends on 1) the characteristics of the cancer cells;2) the host organ microenvironment and 3) the interactions between the cancer cell and the host microenvironment. Recent evidence demonstrates that angiogenesis is an important factor in the development and osteoblastic nature of CaP bone metastasis. Moreover, the degree of angiogenesis correlates with both androgen independence and neuroendocrine (NE) differentiation in CaP. Since expression of vascular endothelial growth factor (VEGF), a powerful angiogenic peptide, is correlated with the metastatic ability of human CaP, we hypothesized that tumor related VEGF expression, and regulators of this process, are important for bone metastasis development. Supporting this notion, our Preliminary Data indicate that: 1) VEGF expression is necessary for CaP growth in vivo and alters this growth in an organ specific fashion;2) Following CaP cell arrest in target organs, tumor VEGF expression is induced preferentially in bone;3) Small GTPase Rap is involved in mediating VEGF and Prostate Specific Antigen (PSA) expression potentially playing a role in androgen independent CaP;4) Focal Adhesion Kinase (FAK) is involved in mediating both VEGF expression and early bone colonization in CaP. These observations lead us to formulate the Guiding Hypothesis VEGF and its regulators FAK and Rap, play critical roles in CaP progression by affecting angiogenesis, androgen dependence and neuroendocrine differentiation. We will test this hypothesis by studies with the following Specific Aims: Aim 1. Understand the role of tumor VEGF in CaP bone metastasis;Aim 2. Evaluate the role of FAK in prostate carcinogenesis, progression and its relationship to VEGF in these processes;Aim 3. Establish if Rap contributes to CaP bone metastasis and androgen independence and its relationship to VEGF in these processes. Program Interactions will be with 1) Project 2 (S. Parsons) to evaluate the role of VEGF in the enhancement of growth and bone metastasis by NE-cells;2) Project 3 (Weber), since Rap affects both tumor angiogenesis and androgen dependence;3) Tissue Analysis Core for the immunohistochemical evaluation of xenograft and transgenic CaP primary tumors and bone metastases, laser microdissection and bone morphometry to determine the contribution of VEGF to the osteoblastic phenotype;4) Cell Culture and Animal Core will provide prostate cell lines and whole animal xenograft imaging;5) in vivo experiments are designed with biostatistics support of the Administrative Core. Conclusions: Completion of these aims will provide relevant information on the mechanisms underlying prostate cancer progression and metastasis and may lead to therapies that interfere with this process in patients.